Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD can also be caused by mutations in the alpha-synuclein, parkin, DJ-I and PINK1 genes. Elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial parkinsonism will likely provide important clues to the pathogenic mechanisms responsible for idiopathic PD. The recessive inheritance mode of the mutations and the existence of large exonic deletions in the, parkin, DJ-1 and PINK1 genes indicate that loss of function of a single gene product can lead to clinical manifestations of parkinsonism and selective dopaminergic degeneration. We take advantage of the identification of these genes to study the mechanisms by which loss-of-function mutations in these genes result in manifestations of parkinsonian features through the generation of mutant mice. Our previous generation and analysis of parkin-/- mice have shown nigrostriatal deficits and mitochondrial dysfunction in the absence of loss of dopaminergic neurons, suggesting that these functional deficits likely precede neurodegeneration, and that mitochondrial dysfunction may be causal in PD pathogenesis. In this proposal, we hypothesize that loss-of function mutations in the DJ-1 gene alter the normal physiology of dopaminergic neurons in the substantia nigra, ultimately leading to their degeneration and production of parkinsonian phenotypes. To test this hypothesis, we propose the following three Specific Aims. First, we will generate and analyze DJ-1-/-null mice for disruption of normal dopaminergic neurotransmission, loss of dopaminergic neurons and motor impairments. Second, we will determine whether loss of DJ-1 function results in mitochondrial dysfunction and increased oxidative damage. Third, since mouse models bearing mutations in a single pathogenic gene, such as parkin-null mice and alpha-synuclein transgenic mice, fail to develop the cardinal feature of PD, namely selective dopaminergic degeneration, we will investigate whether the presence of two pathogenic mutations accelerates the dysfunction and degeneration of dopaminergic neurons in mice deficient in both DJ-1 and parkin. Our long-term goal is to develop a genetic mouse model that recapitulates all central features of PD and to characterize the molecular pathways responsible for PD pathogenesis.